Estrogen therapy in postmenopausal women is associated with reduced cardiovascular events, the mechanism of which is unclear. Because oxidation of low density lipoprotein may contribute to atherogenesis, we measured susceptibility of low density lipoprotein to peroxidation before and following infusion of 17 BETA-estradiol 20 ng/min for 20 minutes into the brachial artery of 18 postmenopausal women. Low density lipoprotein oxidation was assessed by the formation of conjugated dienes following the addition of CuCl2 using spectrophotometric absorbance at 234 nm. We measured the lag time to onset of oxidation and the maximal oxidation rate. Following the infusion of estradiol, associated with an increase in the venous estradiol level from 15plus/minus21 to 435plus/minus186 pg/ml (mean plus/minus standard deviation), the lag time to onset of oxidation increased significantly by 33 minutes with a significant decrease in the maximum oxidation rate. Following 3 weeks of transdermal 17beta-estradiol to 12 women, associated with venous estradiol level of 126plus/minus43 pg/ml, the lag time to onset of oxidation was prolonged by 48 minutes compared to baseline measurements. Ten women returned for repeat measurement of low density lipoprotein oxidation 1 month after discontinuation of the estradiol patch. The lag time to oxidation returned to baseline values. Thus, we conclude that acutely and chronically administered estradiol decreases the oxidative capacity of low density lipoprotein in postmenopausal women and may contribute to the antiatherogenic effect of estrogen.